The objective of this project is to determine the specific cause of bile acid malabsorption in cystic fibrosis of the pancreas and to simplify the diagnosis of this malabsorption. The accepted theory is that undigested nutrients inhibit bile acid absorption. Definitive studies however have not been carried out and the question remains unresolved. First, animal studies will be conducted to define bile acid adsorption and the effects of undigested dietary nutrients on this process both in vitro and in vivo. We have demonstrated that undigested lipid soluble nutrients inhibit intestinal bile acid diffusion but not active transport. Furthermore, our results demonstrate that water soluble nutrient macromolecules do not inhibit bile acid absorption. This is contrary to the intraluminal theory and may indicate mucosal involvement in this disease. Since bile acid absorption is sodium dependent, experiments will be repeated testing sodium adsorption in bile acid media with and without undigested nutrients. An animal model for pancreatic insufficiency is being developed to assist in these studies. Using these data, bile acid adsorption by intestinal biopsy tissue from cystic fibrosis patients will be examined along with controls. If bile acid adsorption in this tissue is normal in physiologic environment, nutrient effects will be examined to support the theory. Our preliminary results with cystic fibrosis patients, however, indicate that bile acid adsorption by ileal mucosa in a physiologic environment is abnormal, suggesting a cellular defect. If bile acid absorption is abnormal in this tissue, the theory has been disproven and an important facet in this disease has been revealed, hopefully providing new insight into the cause of cystic fibrosis. It would also provide a clearer understanding of bile acid malabsorption leading to more effective management. The project will also focus on improving the diagnosis of malabsorption by radioimmunoassay, thereby providing the physician with a simple and less cumbersome diagnostic test to assess the extent of involvement of cystic fibrosis.